Protein tyrosine phosphorylation plays an important role in the regulation of cellular signal transduction, cell growth and differentiation. The level of tyrosine phosphorylation is controlled by the equilibrium of the activities of the protein tyrosine kinases (PTK) and protein tyrosine phosphatases (PTP) (Cantley, L. C. et al., 1991, Cell, 64, pp.281-302; Fischer, E. H. et al., 1991, Science, 253, pp.401-406; Alexander, D. R. and Cantrell, D. A., 1989, Immunol. Today, 10, pp.200-205; Tonks, N. K. and Charbonneau, H., 1989, Trends Biochem. Sci., 14, pp.497-500; Saito, H. and Streuli, M. 1991. Cell Growth And Differentiation, 2, pp.59-65; Gautier, J. et al., 1991, Cell, 67, pp.197-211; Zheng, X. M. et al., Nature, 359, pp.336-339). It is well documented that tyrosine kinase activities play an important role in the growth and the differentiation of bone cells. M-CSF and its receptor c-fms were shown to be crucial in osteoclast development. Recently Soriano et al. reported that disruption of c-src proto-oncogene, by homologous recombination, induced osteoporosis, that is characterized by the reduction of bone resorption due to impairment of osteoclastic function (Soriano, P. et al., 1991, Cell, 64, pp.693-702; Boyce, B. F. et al., 1992, J.Clin.Invest:, 90, pp.1622-1627). In both in vivo and in vitro experiments it was demonstrated that FGF, IGF-I and IGF-II are important for the osteoblast functions. These findings suggest that the control of tyrosine phosphorylation is clearly important for bone cells.
As mentioned above, protein tyrosine phosphorylation is tightly balanced by the opposing actions of protein tyrosine kinases and protein tyrosine phosphatases. Treatment of bone cells with orthovanadate, a PTPase inhibitor, resulted in the stimulation of cell proliferation and the synthesis of bone collagen (Lau et al. Endocrinology, 1988, 123, pp. 2858-2867). In organ cultures, vanadate treatment inhibited the stimulation of bone resorption induced by treatment with PTH (Krieger and Tashjian, Endocrinology, 1983, 113, pp. 324-328). Taken together, these findings suggest that PTPases play an important function in bone cells: